The present invention relates to benzimidazole derivatives, to their preparation and to their therapeutic application.
The present invention relates to compounds corresponding to formula (I): 
in which:
R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a nitro group or a C1-C4 alkoxy group,
R2 and R2xe2x80x2 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
X represents a nitrogen atom or a carbon atom,
n is equal to 1 or 2,
m is equal to 1 or 2,
and, when X represents a nitrogen atom:
R3 represents a hydrogen atom or a C1-C4 alkyl group, to give compounds of formula (I) comprising a quaternary ammonium, or alternatively does not exist, to give compounds of formula (I) comprising a secondary or tertiary amine,
R4 represents
a hydrogen atom,
a C1-C6 alkyl group,
a C3-C7 cycloalkyl group,
a C3-C7 heterocycloalkyl group optionally substituted with a C1-C4 alkyl group or a group xe2x80x94COOR, in which R represents a C1-C6 alkyl group,
a group xe2x80x94(CH2)p-heteroaryl, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from pyridyl, aminopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl and thienyl groups, the said heteroaryl group optionally being substituted with a C1-C4 alkyl group,
a heteroarylcarbonyl group, the heteroaryl group being chosen from furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and imidazolyl groups,
a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,
a (C1-C6)alkylcarbonyl group,
a group xe2x80x94(CH2)pCOOR in which p may range from 0 to 4 and in which R represents a C1-C6 alkyl group,
a phenylsulphonyl group optionally substituted on the phenyl nucleus with a halogen atom, a trifluoromethyl group, a C1-C4 alkyl group, a nitro group or a C1-C4 alkoxy group, or alternatively
a xe2x80x94(CH2)p-phenyl group, in which p may range from 0 to 4 and in which the phenyl group is optionally substituted, in the ortho and/or meta and/or para position, with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenyl group, a C1-C4 alkylamino group, a C1-C4 dialkylamino group, an xe2x80x94NHCHO group or a group xe2x80x94NHCORxe2x80x2, in which Rxe2x80x2 represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,
and, when X represents a carbon atom:
R3 represents a hydrogen atom, a group xe2x80x94NR5R6, a group xe2x80x94N(R5)3+, a group xe2x80x94NHCOR7, a group xe2x80x94CONHR5, a group xe2x80x94COR7, an xe2x80x94NHCONH2 group, an xe2x80x94OH group or a xe2x80x94CH2OH group,
R4 represents
a hydrogen atom,
a xe2x80x94(CH2)p-phenyl group, in which p may range from 0 to 4 and in which the phenyl group is optionally substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a halogen atom, a trifluoromethyl group or a C1-C4 alkoxy group,
a xe2x80x94(CH2)p-heteroaryl group, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group, a pyridyl group, an aminopyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinyl group, or alternatively
a group xe2x80x94(CH2)tNR7R8, in which t is equal to 0 or 1,
with the proviso that when R4 represents a group xe2x80x94NR7R8, R3 is other than the groups xe2x80x94NR5R6, xe2x80x94NHCOR7, xe2x80x94NHCONH2 and xe2x80x94OH,
R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
R7 and R8 represent, independently of each other, a C1-C4 alkyl or C1-C4 alkoxy group or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, to form, for example, a 1-piperidyl group, a 1-pyrrolidinyl group or a 1-piperazinyl group, this ring optionally being substituted, on a carbon atom or on a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached to form a quaternary ammonium, with a C1-C4 alkyl group or a group xe2x80x94COORxe2x80x3, in which Rxe2x80x3 represents a phenyl or (C1-C4)alkylphenyl group,
with the exclusion of the two compounds for which R1=R2=R2xe2x80x2=R3=H, X=C, n=m=1 and R4 represents either a 4-imidazolyl group or a 5-methyl-4-imidazolyl group.
These two compounds are disclosed in patent application EP 646 583, as compounds 16 and 17 in the table, as 5-HT3 and 5-HT4 type serotoninergic receptor ligands.
The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also the mixtures thereof, including racemic mixtures, form part of the invention.
The compounds of the invention may exist in the form of bases or of addition salts with pharmaceutically acceptable acids. Such addition salts also form part of the invention.
In the context of the present invention, the term:
xe2x80x9ca (Cq-Cr)alkyl groupxe2x80x9d means a linear or branched saturated aliphatic group comprising from q to r carbon atoms, q and r being integers; mention may be made in particular of methyl, ethyl, propyl, isopropyl, n-propyl, butyl, isobutyl, tert-butyl, n-butyl, pentyl, etc. groups;
xe2x80x9ca halogen atomxe2x80x9d means a fluorine, a chlorine, a bromine or an iodine;
xe2x80x9ca C3-C7 cycloalkyl groupxe2x80x9d means a cyclic alkyl group containing from 3 to 7 carbon atoms; mention may be made in particular of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups;
xe2x80x9ca C3-C7 heterocycloalkyl groupxe2x80x9d means a cyclic alkyl group containing from 3 to 7 carbon atoms and also one or more hetero atoms, for example a nitrogen atom; mention may be made in particular of piperidyl groups;
xe2x80x9ca (C1-C4)alkoxyphenyl groupxe2x80x9d means a group of formula xe2x80x94Oxe2x80x94(CH2)x-phenyl, in which x may range from 1 to 4.
Among the compounds of formula (I) which are the subjects of the present invention, mention may be made of the preferred compounds for which:
R1 represents a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group,
R2 represents a hydrogen atom or a C1-C4 alkyl group,
R2xe2x80x2 represents a hydrogen atom,
X represents a nitrogen atom,
n is equal to 1 or 2,
m is equal to 1 or 2,
R3 represents a hydrogen atom, to give compounds of formula (I) comprising a quaternary ammonium, or alternatively does not exist, to give compounds of formula (I) comprising a secondary or tertiary amine,
R4 represents
a hydrogen atom,
a C1-C6 alkyl group,
a C3-C7 cycloalkyl group,
a pyridyl, pyrimidinyl or pyrazinyl group, optionally substituted with a C1-C4 alkyl group,
a heteroarylcarbonyl group, the heteroaryl group being chosen from a furyl group and a pyridyl group,
a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,
a (C1-C6)alkylcarbonyl group,
a group xe2x80x94(CH2)pCOOR in which p can range from 0 to 4 and in which R represents a C1-C6 alkyl group,
a phenylsulphonyl group,
a phenyl group substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenyl group, a (C1-C4)dialkylamino group, an xe2x80x94NHCHO group or a group xe2x80x94NHCORxe2x80x2, in which Rxe2x80x2 represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,
a xe2x80x94(CH2)p-phenyl group, in which p can range from 0 to 4,
a xe2x80x94(CH2)p-pyridyl group, in which p can range from 0 to 4,
a xe2x80x94(CH2)p-thienyl group, in which p can range from 0 to 4,
a (C3-C7)heterocycloalkyl group optionally substituted with a C1-C4 alkyl group or a group xe2x80x94COOR, in which R represents a C1-C6 alkyl group,
or alternatively the preferred compounds for which:
R1 represents a hydrogen atom,
R2 and R2xe2x80x2 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
X represents a carbon atom,
n is equal to 1 or 2,
m is equal to 1,
R3 represents a hydrogen atom, a group xe2x80x94NR5R6, a group xe2x80x94N(R5)3+, a group xe2x80x94NHCOR7, a group xe2x80x94CONHR5, an xe2x80x94NHCONH2 group, an xe2x80x94OH group or a xe2x80x94CH2OH group,
R4 represents
a hydrogen atom,
a benzyl group (namely a xe2x80x94(CH2)p-phenyl group in which p is equal to 1),
a phenyl group optionally substituted with one to three groups chosen, independently of each other, from: a C1-C4 alkyl group, a nitro group, an amino group, a halogen atom, a trifluoromethyl group or a C1-C4 alkoxy group,
a heteroaryl group chosen from an imidazolyl group, optionally substituted with a C1-C4 alkyl group, or a pyridyl group,
a group xe2x80x94NR7R8,
with the proviso that when R4 represents a group xe2x80x94NR7R8, R3 is other than the groups xe2x80x94NR5R6, xe2x80x94NHCOR7, xe2x80x94NHCONH2 and xe2x80x94OH,
R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
R7 and R8 represent, independently of each other, a C1-C4 alkyl or C1-C4 alkoxy group, or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, this ring optionally being substituted, on a carbon atom or a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached to form a quaternary ammonium, with a C1-C4 alkyl group or a group xe2x80x94COORxe2x80x3, in which Rxe2x80x3 represents a phenyl or (C1-C4)alkylphenyl group,
with the exclusion of the two compounds for which R1=R2=R2xe2x80x2=R3=H, X=C, n=m=1 and R4 represents either a 4-imidazolyl group or a 5-methyl-4-imidazolyl group.
Among the latter preferred compounds, ones most particularly preferred are the compounds of formula (I) for which:
R1 represents a hydrogen atom, a methyl group or a methoxy group,
R2 represents a hydrogen atom or a methyl group,
R2xe2x80x2 represents a hydrogen atom,
X represents a nitrogen atom,
n is equal to 1 or 2,
m is equal to 1 or 2,
R3 represents a hydrogen atom, to give compounds of formula (I) comprising a quaternary ammonium, or alternatively does not exist, to give compounds of formula (I) comprising a secondary or tertiary amine,
R4 represents
a hydrogen atom,
a C1-C4 alkyl group,
a C6-C7 cycloalkyl group,
a pyridyl, pyrimidinyl or pyrazinyl group, optionally substituted with a C1-C4 alkyl group,
a heteroarylcarbonyl group, the heteroaryl group being chosen from a furyl group and a pyridyl group,
a phenylcarbonyl group, the phenyl group optionally being substituted with a halogen atom,
a (C3-C5)alkylcarbonyl group,
a group xe2x80x94(CH2)pCOOR in which p is equal to 0 or 1 and in which R represents a C1-C4 alkyl group,
a phenylsulphonyl group,
a phenyl group substituted with one to three groups chosen, independently of each other, from: a methyl group, a nitro group, an amino group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a methoxy group, a (C1-C4)alkoxyphenyl group, a dimethylamino group, an xe2x80x94NHCHO group or a group xe2x80x94NHCORxe2x80x2, in which Rxe2x80x2 represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group optionally being substituted with a dimethylamino group,
a xe2x80x94(CH2)p-phenyl group, in which p is equal to 1, 2, 3 or 4,
a xe2x80x94(CH2)p-pyridyl group, in which p can range from 1 to 3,
a xe2x80x94(CH2)p-thienyl group, in which p is equal to 2,
a C6-C7 heterocycloalkyl group optionally substituted with a methyl group or a group xe2x80x94COOR, in which R represents a C1-C4 alkyl group,
or alternatively, the compounds that are most particularly preferred are those of formula (I) for which:
R1 represents a hydrogen atom,
R2 and R2xe2x80x2 represent, independently of each other, a hydrogen atom or a methyl group,
X represents a carbon atom,
n is equal to 1 or 2,
m is equal to 1,
R3 represents a hydrogen atom, a group xe2x80x94NR5R6, an xe2x80x94N(CH3)3+ group, a group xe2x80x94NHCOR7, a group xe2x80x94CONHR5, an xe2x80x94NHCONH2 group, an xe2x80x94OH group or a xe2x80x94CH2OH group,
R4 represents
a hydrogen atom,
a benzyl group,
a phenyl group optionally substituted with one to three groups chosen, independently of each other, from a halogen atom and a trifluoromethyl group,
a heteroaryl group chosen from an imidazolyl group, optionally substituted with a methyl group, or a pyridyl group,
a group xe2x80x94NR7R8,
with the proviso that when R4 represents a group xe2x80x94NR7R8, R3 is other than the groups xe2x80x94NR5R6, xe2x80x94NHCOR7, xe2x80x94NHCONH2 and xe2x80x94OH,
R5 and R6 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
R7 and R8 represent, independently of each other, a C1-C4 alkyl group or together form a saturated 5- to 7-membered ring optionally comprising an additional nitrogen atom, this ring optionally being substituted, on a carbon atom or on a nitrogen atom, including the nitrogen atom to which the groups R7 and R8 are attached to form a quaternary ammonium, with a methyl group or a group xe2x80x94COORxe2x80x3, in which Rxe2x80x3 represents a (C1-C4)alkylphenyl group,
with the exclusion of the two compounds for which R1=R2=R2xe2x80x2=R3=H, X=C, n=m=1 and R4 represents either a 4-imidazolyl group or a 5-methyl-4-imidazolyl group.
In the text hereinbelow, the term xe2x80x9cleaving groupxe2x80x9d means a group which may be readily cleaved from a molecule by heterolytic cleavage of a bond, with departure of an electron pair. This group may thus be readily replaced with another group during, for example, a substitution reaction. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups and references for preparing them are given in xe2x80x9cAdvances in Organic Chemistryxe2x80x9d, J. March 3rd Edition, Wiley Interscience pp. 310-316.
To prepare the compounds of formula (I) in accordance with the invention, the process is performed according to the synthetic scheme 1 below. According to this process, a derivative of formula (II), in which R1, R2, R2xe2x80x2 and n are as defined above and A represents a leaving group, preferably a halogen, are reacted in the presence of an amine of formula (III), in which X, R3, R4 and m are as defined above, in a solvent which may be an alcohol, such as isoamyl alcohol, an ether such as tetrahydrofuran or TGME (triethylene glycol monomethyl ether) or a hydrocarbon such as toluene, at a temperature of between room temperature and the boiling point of the solvent, to give the compound of formula (I). The reaction may be carried out in the presence of a base such as 2,6-dimethyllutidine or sodium tert-butoxide, in the presence of alkali metal halides such as potassium fluoride or in the presence of palladium-based or nickel-based catalysts, as described, for example, in patent application EP 646 583 or in J. Med. Chem. (1986) 29 1178-1183, Tetrahedron Letters (1997) 32 5607-5610, Tetrahedron Letters (1999) 55 12829-12842 and Tetrahedron Letters (1999) 40 6875-6879.
When the compound of formula (I) comprises a free primary or secondary amine function, it may also be obtained by reacting a derivative of formula (II) with an amine of formula (III) in which the said amine function is protected with a conventional amine-protecting group such as a tert-butyl carbamate (BOC). The compound of formula (I) containing a protected amine function, thus obtained, is then treated according to one of the known methods to give the desired compound (I) containing a free amine function. Examples of amine-protecting groups and of deprotection methods are given in particular in T. W. Greene, P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, J. Wiley, Ed., 1991. 
The compounds of formula (II) may be prepared according to Scheme 2 below, according to operating conditions that are known to those skilled in the art, in particular by reacting a compound of formula (IV), in which R1, R2, n and R2xe2x80x2 are as defined above, with a halogenating agent such as phosphoryl chloride. 
The compounds of formula (IV) may be prepared according to a process described in synthetic scheme 2 above. According to one variant of this process, a diamine of formula (V), in which R1, R2, R2xe2x80x2 and n are as defined above, is coupled with a phosgene derivative such as carbonyldiimidazole (CDI). According to another variant, a derivative of formula (VI), in which R1 is as defined above, is alkylated with an alkylating agent of formula (VIII, R=C1-C4 alkyl) in which R2 is as defined above, to give the products of formula (VII) in which n=1 and R2xe2x80x2=H, or with an agent of formula (IX, R=C1-C4 alkyl) and Y is a leaving group, in which R2 and R2xe2x80x2 are as defined above, to give the products of formula (VII) in which n=2. The compounds (VII) thus obtained are then converted into carboxylic acids (VII, R=H) or into acid derivatives such as acid chlorides (VII, R=C1) and then cyclized under operating conditions known to those skilled in the art, to give the intermediates of formula (II) directly. An approach similar to this second variant is described in particular in patent application JP 55111406 or in Tetrahedron Letters (1995) 36 1387-1390.
Alternatively, the compounds of formula (II) in which R2 and R2xe2x80x2 do not represent hydrogen atoms may be prepared from the corresponding compounds (II) in which R2xe2x80x2 represents a hydrogen atom, by alkylation with a reagent of the type R2xe2x80x2 Z in which Z represents a leaving group, preferably iodine. This reaction may be carried out in a solvent such as dimethylformamide, ether or tetrahydrofuran in the presence of a base, according to methods known to those skilled in the art.
The compounds of formulae (III), (V), (VI), (VIII) and (IX) are commercially available or may be prepared according to operating conditions that are known to those skilled in the art.
A subject of the present invention is also the novel synthetic intermediates of formula (II).
The examples which follow illustrate the present invention. The numbers for the compounds given as examples refer to those in the table given later, which illustrates the chemical structures of a number of compounds according to the invention.